HER2低表达乳腺癌临床病理学特征及预后研究

doi:10.16150/j.1671-2870.2024.05.006

摘要/Abstract

摘要：

目的：探讨人表皮生长因子受体2（human epidermal growth factor receptor 2, HER2）低表达乳腺癌的临床病理学特征及预后，并分析影响HER2免疫组化判读一致性的主要因素。方法：收集本中心2021年9月至2022年6月诊治的连续性浸润性乳腺癌病例共237例，由2名乳腺专科病理医师对所有既往病例的HER2免疫组化判读结果分别复核。将HER2结果分为HER2阴性组、低表达组以及阳性组，比较HER2低表达乳腺癌与其他2组的临床病理特征及预后差异。结果：2名医师的判读结果与既往结果的完全一致率为78.9%（187/237），判读不一致的病例中近半数（占48.0%），是由临界表达及肿瘤异质性所致。与HER2阴性(n=49)和阳性(n=75)组相比，HER2低表达(n=113)乳腺癌患者组织学级别以2级为主（P值分别为0.045和<0.001），ER和PR阳性比例显著高（分别为84.1%和77.9%，P值均≤0.001），分子分型以Luminal B型和Luminal A型为主（分别占54.0%和30.1%）。但当调整ER状态后，HER2低表达和阴性组之间所有的临床病理参数均没有统计学差异，包括患者年龄、组织学类型及级别、肿瘤大小、淋巴结转移情况、脉管侵犯、Ki-67指数及分子分型。本研究中位随访时间26个月，生存分析结果显示，不论是否校正ER状态，HER2低表达组和阴性组乳腺癌患者的无病生存期（disease-free survival, DFS）差异均无统计学意义。结论：与HER2阴性乳腺癌相比，HER2低表达乳腺癌的临床病理特征差异主要是由激素受体状态导致，两者短期预后无差异；临界表达及肿瘤异质性是影响HER2判读一致性的主要因素。

关键词: 乳腺癌, 免疫组织化学, HER2低表达, 临床病理学特征, 预后

Abstract:

Objective This study explores the clinicopathological features and prognosis of breast cancer with low expression of human epidermal growth factor receptor 2 (HER2), and analyzes the main factors that influence the consistency of HER2 immunohistochemical interpretation. Methods A total of 237 cases of consecutive invasive breast cancer diagnosed and treated in this center from September 2021 to June 2022 were collected. The HER2 immunohistochemical interpretation results of all previous cases were reviewed by two breast specialist pathologists respectively. The HER2 results were divided into HER2 negative group, low expression group, and positive group. The clinicopathological features and prognosis of HER2 low expression breast cancer were compared with those of the other two groups. Results The perfect concordance rate between the interpretation results of the two pathologists and the previous results was 78.9% (187/237). Nearly half of the cases with inconsistent interpretations (48.0%) were caused by borderline expression and tumor heterogeneity. Compared with the HER2 negative (n=49) and HER2 positive (n=75) groups, patients with HER2 low expression breast cancer (n=113) were mainly grade 2 histological classification (P=0.045 and <0.001, respectively), a significantly higher proportion of ER and PR positivity (84.1% and 77.9%, respectively, both P≤0.001), and were mainly classified as Luminal B and Luminal A molecular subtypes (54.0% and 30.1%, respectively). However, after adjusting the ER status, there was no statistical difference in all clinicopathological parameters between HER2 low expression and negative groups, including patient age, histological type and grade, tumor size, lymph node metastasis, vascular invasion, Ki-67 index, and molecular subtypes. The median follow-up time of this study was 26 months. Survival analysis showed that, regardless of whether ER status was adjusted, there was no statistically significant difference in disease-free survival (DFS) between HER2 low expression and negative groups of breast cancer patients. Conclusions Compared with HER2 negative breast cancer, the difference in clinicopathological features of HER2 low expression breast cancer is mainly caused by hormone receptor status, and there is no significant difference in short-term prognosis between the two， and borderline expression and intratumor heterogeneity are major factors affecting the consistency of HER2 interpretation.

Key words: Breast cancer, Immunohistochemistry, HER2 low expression, Clinicopathological features, Prognosis

中图分类号:

R737.9

阮淼, 笪倩, 许海敏, 董磊, 费晓春. HER2低表达乳腺癌临床病理学特征及预后研究[J]. 诊断学理论与实践, 2024, 23(05): 500-508.

RUAN Miao, DA Qian, XU Haimin, DONG Lei, FEI Xiaochun. Study on clinicopathological features and prognosis of HER2 low expression breast cancer[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(05): 500-508.

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Previous result		Observer 1		Observer 2		Adjusted result		Complete agreement n（%）
HER2	n	HER2	n	HER2	n	HER2	n	Complete agreement n（%）
0	63	0	43	0	45	0	49	43（87.8）
		1+	20	1+	18
1+	57	0	9	0	4	1+	69	36（52.2）
		1+	36	1+	49
		2+	12	2+	4
2+	48	1+	3	1+	2	2+	48	40（83.3）
		2+	40	2+	44
		3+	5	3+	2
3+	69	2+	1	2+	0	3+	71	68（95.8）
		3+	68	3+	69
Total								187（78.9）

Apparent causes	n（%）
Objective factors	24（48.0）
Borderline expression	21
Intratumor heterogeneity of staining	3
Subjective factors	14（28.0）
Previously no carefully evaluated in HPF	12
Observer error	2
Interference factors	12(24.0)
Nonspecific staining of stroma	7
Cytoplasmic staining	5

	HER2-low （n=113）	HER2-negative （n=49）	P value	HER2-positive （n=75）	P value
Age (years)			0.224		0.101
≤50	35(31.0)	20(40.8)		32(42.7)
>50	78(69.0)	29(59.2)		43(57.3)
Histological type			0.231		0.774
IBC, NST	101(89.4)	47(95.9)		68(90.7)
Others	12(10.6)	2(4.1)		7(9.3)
T stage			0.464		0.003
1	59(52.2)	31(63.3)		23(30.7)
2	53(46.9)	18(36.7)		48(64.0)
3	1(0.9)	0		4(5.3)
Histological grade			0.045		<0.001
1	13(11.5)	4(8.2)		0
2	57(50.4)	16(32.6)		17(22.7)
3	43(38.1)	29(59.2)		58(77.3)
LVI			0.400		0.764
Positive	25(22.1)	8(16.3)		18(24.0)
Negative	88(77.9)	41(83.7)		57(76.0)
N stage			0.285		0.516
0	85(75.2)	39(79.6)		52(69.3)
1	16(14.2)	8(16.4)		15(20.0)
2	11(9.7)	1(2.0)		6(8.0)
3	1(0.9)	1(2.0)		2(2.7)
ER			0.001		<0.001
Positive	95(84.1)	30(61.2)		37(49.3)
Negative	18(15.9)	19(38.8)		38(50.7)
PR			0.001		<0.001
Positive	88(77.9)	26(52.9)		27(36.0)
Negative	25(22.1)	23(47.1)		48(64.0)
Ki-67			0.008		<0.001
≤30%	84(74.3)	26(53.1)		37(49.3)
>30%	29(25.7)	23(46.9)		38(50.7)
Intrinsic subtype			0.006		<0.001
Luminal A	34(30.1)	8(16.3)		0
Luminal B	61(54.0)	22(44.9)		38(50.7)
HER2-enriched	0	0		37(49.3)
TNBC	18(15.9)	19(38.8)		0

Item	ER positive			ER negative
Item	HER2-low （n=95）	HER2-negative （n=30）	P value	HER2-low （n=18）	HER2-negative （n=19）	P value
Age (years)			0.195			0.823
≤50	29(30.5)	13(43.3)		6(33.3)	7(36.8)
>50	66(69.5)	17(56.7)		12(66.7)	12(63.2)
Histological type			0.732			0.486
IBC, NST	84(88,4)	28(93.3)		17(94.4)	19(100)
Others	11(11.6)	2(6.7)		1(5.6)	0
T stage			0.125			0.362
1	54(56.8)	23(76.7)		5(27.8)	8(42.1)
2	40(42.1)	7(23.3)		13(72.2)	11(57.9)
3	1(1.1)	0		0	0
Histological grade			0.472			1.000
1	13(13.7)	4(13.3)		0	0
2	55(57.9)	14(46.7)		2(11.1)	2(10.5)
3	27(28.4)	12(40.0)		16(88.9)	17(89.5)
LVI			0.614			0.693
Positive	21(22.1)	5(16.7)		4(22.2)	3(15.8)
Negative	74(77.9)	25(83.3)		14(77.8)	16(84.2)
N stage			0.490			0.566
0	72(75.8)	24(80.0)		13(72.2)	15(78.9)
1	11(11.6)	5(16.7)		5(27.8)	3(15.8)
2	11(11.6)	1(3.3)		0	1(5.3)
3	1(1.0)	0		0	0
PR			0.295			/
Positive	88(92.6)	26(86.7)		0	0
Negative	7(7.4)	4(13.3)		18(100)	19(100)
Ki67（%）			0.591			0.405
≤30	80(84.2)	24(80.0)		4(22.2)	2(10.5)
>30	15(15.8)	6(20.0)		14(77.8)	17(89.5)
Intrinsic subtype			0.356			/
Luminal A	34(35.8)	8(26.7)		0	0
Luminal B	61(64.2)	22(73.3)		0	0
HER2-enriched	0	0		0	0
TNBC	0	0		18(100)	19(100)